Process for preparing a 1-(lower alkyl)-5-nitro-2-imidazolecarboximidate ester

ABSTRACT

This disclosure describes a multistep process for the preparation of certain 2-amino-5-(1-(lower alkyl)-5-nitro-2imidazoyl)-1,3,4-thiadiazoles; the products of the process being useful as antibacterial and antiprotozoal agents.

Qll 1 96 ilniteu States atet Papalioannou [54] PROCESS FOR PREPARING A1- (LOWER ALKYL)-5-NITRO-2- IMIDAZOLECARBOXIMIDATE ESTER [72] Inven r:Christos George Papaioannou, Somifliiliiif': .,,V

[73] Assignee: American Cyanamid Company,

- Stamford, Conn. 22 Filed: April 17,1970

211 Appl. No.: 29,686

[52] US. Cl. ..260/309, 260/240 R, 260/306.8 [51] Int. Cl. ..C07d 49/30[58] Field of Search ..260/306.8 D, 309, 453

[56] References Cited FOREIGN PATENTS OR APPLICATIONS Japan zeq/aqe s p[4 1 Sept. 26, 1972 OTHER PUBLICATIONS Primary Examiner-Alex Maze!Assistant Examiner-R. J. Gallagher Attorney--Edward A. Conroy, Jr.

[5 7] ABSTRACT This disclosure describes a multistep process for thepreparation of certain 2-amino-5-[l-(lower alkyl)-5-nitro-2-imidazoyl1-l,3,4-thiadiazoles; the products of the process beinguseful as antibacterial and antiprotozoal agents.

2 Claims, No Drawings 1 PROCESS FOR PREPARING A l-(LOWER ALKYLJ-S-NITRO-Z-IMIDAZOLECO W 111: ES'I'ER BRIEF SUMMARY OF THE INVENTION Thisinvention relates to a novel preparative method involving the reactionof a mixed anhydride of an N- aroyl- 1 -(lower alkyl)-5-nitro-Z-imidazolecarboximidic acid and a benzoic acid (I) with alower alkanol in the presence of a strong base to afford thecorresponding lower alkanol ester of l-(lower alkyl)-S-nitro-2- DETAILEDDESCRIPTION OF THE INVENTION The novel process of the present inventionproceeds asset forth in the following reaction scheme:

7 ON i i I /Rs 32, OgN- wherein R and R are the' same or different andare each lower alkyl, R and R are the same or different and areeach-phenyl or para-substituted phenyl, and R 1 and R are the same ordifferent and are each hydrogen or lower alkyl. Suitable lower alkylgroups contemplated by the present invention are those having up to fourcarbon atoms such as, for example, methyl, ethyl, n-propyl, iso-butyl,sec-butyl, etc. Suitable para-substituted phenyl groups contemplated bythe present invention are, for example, p-tolyl, p-chlorophenyl,pbromophenyl, p-nitrophenyl, p-methoxyphenyl, pacetoxyphenyl,p-acetylphenyl, p-acetamidophenyl, and the like. In accordance with theabove reaction scheme, the conversion of the mixed anhydrides (I) to thecorresponding l-(lower alkyl)-5-nitro-2- imidazolecarboximidate esters(II) is accomplished with a strong base in a lower alkanol solvent (R014; e.g., methanol, ethanol, isopropanol, n-butanol, etc.) at atemperature of from about 0C. to about 100C., preferably -30C., for aperiod of time of a few hours or more. The esters (II) are notisolatedbut are converted in situ to the 1-substituted-3-thiosemicarbazides(III). Suitable strong bases are, preferably, alkali metal hydroxides,cyanides, or alkoxides such as sodiimidazolecarboximidic acid (II);condensing the 1- V um hydroxide, potassium hydroxide, sodium cyanide,potassium cyanide, potassium tert-butoxide, sodium methoxide, sodiumethoxide, and the like. While only a catalytic amount of base in excessof and in addition to a stoichiometric equivalent is required for thereaction, two or even 3 mole equivalents of base may be employed.However, larger excesses of strong base do not appear to have anyadvantage.

The conversion of the esters (II) to the correspondingl-substituted-3-thiosemicarbazides (III) is accom plished in situ bytreatment of the esters (II) with an equimolar amount of athiosemicarbazide of the formula:

wherein R and R are as hereinabove defined. An amount of an organiccarboxylic acid such as acetic, benzoic, propionic, butyric, etc. isadded sufficient to first neutralize the reaction mixture and thenprovide a catalytic or greater amount of the acid. This condensa- 45tion is then carried out at a temperature of from about 0C. to about C.,preferably 20-30C., for a period of time of a few hours or more in thelower alkanol solvent. Alternatively, a catalytic amount of a strongmineral acid or a strong organic acid, such as benzenesulfonic acid ortrifluoroacetic acid, may be used provided the temperature is heldbetween about 0C. and about 30C. The product (III) is removed byfiltration, treated with sodium bicarbonate solution, washed and dried.

The cyclization of the 1-substituted-3-thiosemicarbazides (III) to thecorresponding 2-amino-5-[l-(loweralkyl)-5-nitro-2-imidazolyl]-l,3,4-thiadiazoles (IV) is accomplished bymeans of a strong mineral acid or a strong organic acid in a loweralkanol (e.g., methanol, ethanol, isopropanol, etc.) as solvent.Suitable mineral acids which may be employed are, for example, hydrogenfluoride, conc. hydrochloric, conc. hydrobromic, conc. sulfuric, and thelike. Among the strong organic acids that can be used arep-toluenesulfonic acid, trifluoroacetic acid, and the like. The reactionis best carried out at a temperature of from about 0C. to about C,conveniently at the reflux temperature, for a period of about an hour,more orless.

The product (IV), which separates from the reaction mixture, is removedby filtration, washed and dried.

By referring to the reaction scheme it can be seen that the mixedanhydride (I) can be converted to the thiadiazole (IV) in a telescoped"process. This involves the steps of 1) treating the mixed anhydride (1)with at least 1 mole equivalent plus a catalytic amount, preferably 2mole equivalents, of a strong base, as defined hereinabove, in thepresence of a lower alkanol solvent, also as described hereinabove; (2)treating the thus formed mixture with a thiosemicarbazide with acatalytic amount of an organic or mineral acid present, and (3) heatingthe thus formed reaction mixture with a mineral or strong organic acid,preferably selected from the group consisting of hydrohalic acids,sulfur containing mineral acids, p-toluenesulfonic acid, ortrifluoroacetic acid.

The starting materials (I) for the novel process of the presentinvention may be readily prepared from a 1- (loweralkyl)-2-methyl-5-nitroimidazole (VII) in accordance with the followingreaction scheme:

(1) hydrolysis (2) nitrosation wherein R, R and R are as hereinabovedefined and X is chloro or bromo. As set forth above, condensation of al-( lower alkyl)-2-methyl-5-nitroimidazole (VII) with an aroyl halide (RCOX) afiords the corresponding benzoate or para-substituted benzoateester of l-( lower alkyl)-5-nitro-a-aryl-2-imidazoleethenol (VI). Thiscondensation is best carried out in an inert solvent such astetrahydrofuran, diglyme, toluene, and the like in the presence of atertiary amine such as trimethylamine, triethylamine, ordiisopropylethylamine at a temperature of about 25C. to 125C. for aperiod of time of 16-24 hours. From about 2 to about 2.5 moleequivalents of the aroyl halide (R COX) are preferably employed and asufficient amount of tertiary amine is is accomplished by adding anaqueous solution of sodium nitrite or potassium nitrite and stirring thereaction mixture at about room temperature for a period of time of 3-6hours.

The so obtained l-oximino-1-[ l-(lower alkyl)-5-nitro-2imidazolyl]-2-arylglyoxal (V) is converted to the correspondingmixed anhydride of N-aroyl-l- (loweralkyl)-5-nitro-2-imidazo1ecarboximidic acid and a benzoic acid (I) bytreatment with an aroyl halide (R COX). The conversion of (V) to (I) isbest carried out in an inert solvent such as acetonitrile, nitromethane,dimethylformamide, ethyl acetate, benzene, toluene, o-dichlorobenzene,etc. (although excess of the aroyl halide can also be used as thesolvent) at a temperature of about 25C. to 150C., preferably at atemperature of from about C. to about 100C. The reaction generallyrequires from about 30 minutes to 2 hours for completion but this timemay be extended if desired. It is usually found to be practical toconduct the reaction employing a stoichiometric excess of the aroylhalide (R COX) reactant. A slight excess is generally sufficient to giveoptimum product yields but on occasion it may be desirable to employ alarge excess, for example, 2 or 3 mole equivalents of aroyl halide (RCOX) per mole of (V). Larger excesses of aroyl halide may be used butthere is generally no advantage to be gained in product yield.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 -filtered, washed with water, and dried. There is obtained47.7 grams, 97 percent, of l-methyl-S-nitro-aphenyl-Z-imidazoleethenolbenzoate, m.p. 205207C.

EXAMPLE 2 Preparation of imidazoleethenol benzoate The procedure ofExample 1 is repeated, substituting an equimolar amount ofl-ethyl-2-methyl-5- nitroimidazole for the l,2-dimethyl-5-nitroimidazoleemployed in that example. There is thus obtained the 1- used to bothcatalyze the reaction and to react with the 55ethyl-5-nitro-a-phenyl-2-imidazoleethenol benzoate.

hydrogen halide produced.

The l-(lower imidazoleethenol arylcarboxylate (VI) is converted to thecorresponding l-oximino-1-[ l-(lower alkyl)-5-nitro2-imidazolyl]-2-arylglyoxal (V) by hydrolysis to the intermediatel-(lower alkyl)-5-nitro-a-aryl-2- imidazoleethenol (not isolated)followed by nitrosation in situ. The hydrolysis step is best carried outin aqueous ethanol as solvent with a strong mineral acid (e.g., Cone.hydrochloric, conc. sulfuric, etc.) at the reflux temperature for aperiod of time of 4-8 hours. The resulting solution is cooled to 10-20C.and nitrosation alkyl)-S-nitro-a-aryl-2- EXAMPLE 3 Preparation ofimidazoleethenol p-toluate By replacing the benzoyl chloride employed inExample 2 with an equimolar quantity of p-toluyl chloride and followingsubstantially the same procedure of Example 2, there is obtained thel-ethyl- 5-nitro-a-(p-tolyl)-2-imidazoleethenol p-toluate.

EXAMPLE 4 Preparation of l-isopropyl-5-nitro-a-(p-chlorophenyl)-l-ethyl-5-nitro-a-phenyl-Z- l-ethyl-5-nitro-a-(p-tolyl)-2- IZ-imidazoleethenol p-chlorobenzoate Following the general procedure ofExample 1, lisopropyl-Z-methyl-S-nitroimidazole is treated withpchlorobenzoyl chloride to give thel-isopropyl-5-nitroa-(p-chlorophenyl)-2-imidazoleethenolpchlorobenzoate.

EXAMPLE 5 EXAMPLE 6 Preparation of l-oximinol l-methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal A mixture of 60 grams, 0.172 mole, ofl-methyl-S- nitro-a-phenyl-2-imidazoleethenol benzoate, 240 ml. ofwater, 240ml. of ethanol, and 200 ml. of 37 percent hydrochloric acid isrefluxed for 6 hours. The resulting solution is allowed to cool to roomtemperature and then cooled in an ice bath to l7-20C. A solution of 35grams, 0.507 mole, of sodium nitrite in 100 ml. of water is added slowlyover a period of about 1 hour, maintaining the temperature between aboutl7-20C. The resulting suspension is stirred at about room temperaturefor 5 hours, the product is filtered, washed with 500 ml. of water, then75 ml. of acetone, and dried. There is obtained 41.7 grams, 89 percent,of l-oximino-1-( l-methyl-5-nitro-2-imidazolyl )-2-phenylglyoxal, m.p.l87-l 88C. (dec.).

EXAMPLE 7 Preparation of l-o'ximinol l-ethyl-5-nitro-2-ir'nidazolyl)-2-phenylglyoxalv In place of thel-methyl-5-nitro-a-phenyl-2- imidazoleethenol benzoate of Example 6,there is employed an equimolar quantity of l-ethyl-S-nitro-aphenyl-2-imidazoleethenol benzoate whereby the l-oximino- 1 l-ethyl-S-nitro-2-imidazolyl )-2 -phenylglyoxal is obtained in equally goodyield.

EXAMPLE 8 Preparation of l -oximinol l -ethyl-5-nitro-2-imidazolyl)-2-(p-tolyl)glyoxal The procedure of Example 6 is repeated,substituting an equimolar amount of l-ethyl-5-nitro-a-(ptolyl)-2-imidazoleethenol p-toluate for thel-methyi-S-nitro-aphenyl-Z-imidazoleethenol benzoate employed in thatEmu: 10

Preparation of l -oximinol l -isobutyl-5-nitro-2-imidazolyl)-2-(p-acetoxyphenyDglyoxal Following the general procedure ofExample 6, l isobutyl-5-nitro-a-( p-acetoxyphenyl )-2- imidazoleethenolp-acetoxy-benzoate is hydrolyzed and nitrosated to give thel-oximino-l-( l-isobutyl-S-nitro-2-imidazolyl)-2-(p-acetoxyphenyl)glyoxal.

EXAMPLE I 1 Preparation of the mixed anhydride ofN-benzoyl-lmethyl-S-nitro 2-imidazolecarboximidic acid and benzoic acidA mixture of 2.74 grams, 0.01 mole, ofl-oximino-ll-methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal and 10 ml.,0.087 mole, of benzoyl chloride, is heated at about 95C. for about 2hours. The mixture is cooled, filtered, washed with 30 ml. of toluene inportions and dried. There is obtained 3.60 grams, 95 percent, of themixed anhydride of N-benzoyl-l-methyl-5-nitro-2- imidazolecarboximidicacid and benzoic acid, m.p. 222224C.

EXAMPLE 12 Preparation of the mixed anhydride ofN-benzoyl-lmethyl-5-nitro-2-imidazolecarboximidic acid and benzoic acidA mixture of 5.00 grams, 0.0182 mole, of l-oximinol l-methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal, 3 .2 ml., 0.0274 mole, ofbenzoyl chloride, and 30 ml. of acetonitrile is refluxed for 2 hours.The reaction mixture is cooled, filtered, washed twice with methanol anddried. There is obtained 6.57 grams, 95 percent, of the mixed anhydride,m.p. 222-224C.

EXAMPLE 13 Preparation of the mixed anhydride ofN-benzoyl-lmethyl-S-nitro-Z-imidazolecarboximidic acid and 4-nitrobenzoic acid This compound is prepared by the method described inExample 12. From 5.00 grams ofl-oximino-l-(lmethyl-S-nitro-Z-imidazolyl)-2-phenylglyoxal and 5.08grams of 4-nitrobenzoyl chloride is obtained the mixed anhydride ofN-ben'zoyl-l-methyl-S-nitro-Z- imidazolecarboximidic acid and4-nitrobenzoic acid, m.p. 2l4-2l5C.

EXAMPLE 14 Preparation of the mixed anhydride ofN-benzoyl-lmethyl-5-nitro-2-imidazolecarboximidic acid and 4-methoxybenzoic acid This compound is prepared by the method describedexample- There is thus obtained the in Example 12. From 5.00 grams ofl-oximino-l-(L ethyl-5-nitro-2-imidazolyl)-2-(p-toly1)glyoxal.

EXAMPLE 9 Preparation of l -oximinol -isopropyl-5-nitro-2-imidazolyl)-2-(p-chlorophenyl)glyoxal By replacing thel-methyl-5-nitro-a-phenyl-2- imidazoleethenol benzoate employed inExample 6 with an equimolar quantity ofl-iSopropyl-S-nitro-a-(pchlorophenyl)-2-imidazoleethenolp-chlorobenzoate and following substantially the same proceduredescribed in Example 6, there is obtained the l-ox iminoll-isopropyl-5nitro-Z-irnidazolyl)-2-(pchlorophenyl)-glyoxal.

methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal and 4.67 grams of anisoylchloride is obtained the mixed anhydride ofN-benzoyll-methyl-5-nitro-2-imidazolecarboximidic acid and4-methoxybenzoic acid, m.p. 201203C.

EXAMPLE 15 Preparation of the mixed anhydride ofN-benzoyl-lethyl-5-nitro-Z-imadazolecarboximidic acid and benzoic acidThe procedure of Example 11 is repeated, substituting an equimolaramount of 1 -oximino-l-(l-ethyl-5-nitro-Z-imidazolyl)-2-phenylglyoxalemployedin that i anhydride example.There is thus obtained the mixed anhydride ofN-benzoyl-l-ethyl--nitro-2-imidazolecarboximidic acid and benzoic acid.

EXAMPLE 16 Preparation of the mixed anhydride ofN-(p-toluyl)-lethyl-5-nitro-2-imidazolecarboximidic acid andpbromobenzoic acid Following the general procedure of Example 12,loximino-1-( 1-ethyl-5-nitro-2-imidazo1yl)-2-(ptolyl)glyoxal is treatedwith p-bromobenzoyl bromide to give the mixed anhydride ofN-(p-toluyl)-l-ethyl-5- nitro-2-imidazolecarboximidic acid andpbromobenzoic acid.

EXAMPLE 17 Preparation of the mixed anhydride of N-(pchlorobenzoyl l-isopropyl-5-nitro-2-imidazolecarboximidic acid and p-acetylbenzoic acidFollowing the general procedure of Example 12, 1- oximino-l-(1-isopropyl-5-nitro-2-imidazolyl)-2-(pchlorophenyl)glyoxal is treatedwith p-acetylbenzoyl bromide to give the mixed anhydride ofN-(pchlorobenzoyl l -isopropyl-5-nitro-2-imidazole-carboximidic acid andp-acetylbenzoic acid.

EXAMPLE 18 Preparation of the mixed anhydride of N-(p-acetoxybenzoyl l-isobutyl-5-nitro-2-imidazolecarboximidic acid and p-acetamidobenzoicacid Following the general procedure of Example 12, 1- oximino-1-(1-isobutyl-5-nitro-2-imidazolyl)-2-( pacetoxyphenyl)glyoxal is treatedwith pacetamidobenzoyl chloride to give the mixed anhydride ofN-(p-acetoxybenzoyl l -isobutyl-5-nitro-2- imidazolecarboximidic acidand p-acetamidobenzoic acid.

EXAMPLE 19 Preparation of l-(1-methyl-S-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide A mixtureof 3.78 grams, 0.010 mole, of the mixed of N-benzoyll-methyl-S -nitro-2-imidazolecarboximidic acid and benzoic acid, 20 ml. of methanol and 0.81gram, 0.015 mole, of sodium methoxide is stirred at room temperature for2.5 hours. Thiosemicarbazide, 0.91 gram, 0.010 mole, and 1 ml. ofglacial acetic acid are added and the mixture is stirred at roomtemperature for an additional 4 hours. The reaction mixture is thencooled in ice and filtered. The red-orange residue is slurried with a 20percent solution of sodium bicarbonate and stirred for 1 hour,

filtered, washed with water and methanol, and dried.

There is obtained 1.70 grams of product, m.p. l86-20 1C.Recrystallization from a mixture of ethanol and dimethyl-formamide givesa product with a m.p. of 2082l0C. (dec.

mixed anhydride of N-benzoyl-l-methyl-5-nitro-2- imidazolecarboximidicacid and 4-nitrobenzoic acid is treated with4-isopropyl-3-thiosemicarbazide to give the l-(l-methyl-5-nitro-Z-imidazole-carboximidoyl)-4-isopropyl-3-thiosemicarbazide.

EXAMPLE 21 EXAMPLE 22 Preparation of l-(l-ethyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide Followingthe general procedure of Example 19, the mixed anhydride of N-benzoyll-ethyl-5-nitro-2- imidazolecarboximidic acid and benzoic acid is treatedwith thiosemicarbazide to give the 1-( l-ethyl-5-nitro-2-imidazolecarboximidoyl )-3-thiosemicarbazide.

EXAMPLE 23 Preparation ofl-(l-ethyl5-nitro-2-imidazolecarboximidoyl)-4,4-dimethyl-3-thiosemicarbazideFollowing the general procedure of Example 19, the mixed anhydride ofN-(p-toluyl)-l-ethyl-5-nitro-2- imidazolecarboximidic acid andp-bromobenzoic acid is treated with 4,4-dimethyl-3-thiosemicarbazide togive the l-( 1-ethyl-5-nitro-2-imidazolecarboximidoyl4,4-dimethyl-3-thiosemicarbazide.

EXAMPLE 24 Preparation of l-( l-methyl-5-nitro-2imidazolecarboximidoyl)-3-thiosemicarbazide A mixture of ml. ofn-butanol, 1.40 grams, 0.026 mole, of sodium methoxide and 7.56 grams,0.020 mole, of the mixed anhydride of N-benzoyl-l-methyl-S-nitro-2-imidazolecarboximidic acid and benzoic acid is stirred at roomtemperature for 3 hours. Thiosemicarbazide, 1.82 grams, 0.020 mole, and3 ml. of glacial acetic acid are added and the mixture is stirred atroom temperature for an additional 4 hours. The reaction mixture iscooled in ice, filtered, washed successively with four l-ml. portions ofmethanol, ml of water, and 4 l-ml. portions of methanol, and dried. Theredorange residue is slurried with a 20 percent sodium bicarbonatesolution, stirred for 1 hour, filtered, washed thoroughly with water anddried. There is obtained 2.5 grams of product, m.p. 189202C. (dec.),which was recrystallized from a mixture of ethanol and dimethylformamide to give a m.p. of 209-2l2C. (dec.).

EXAMPLE 25 Preparation of l-(1-isopropyl-5-nitro-2-imidazolecarboximidoyl)-4-methyl-3-thiosemicarbazideFollowing the general procedure of Example 24, the mixed anhydride ofN-(p-chlorobenzoyl)-l-isopropyl- 5-nitro-2-imidazolecarboximidic acidand p-acetylbenzoic acid is treated with 4methyl-3-thiosemicarbazide togive the l-( l-isopropyl-S-nitro-Z -imidazolecarboximidoyl)-4-methyl-3-thiosemicarbazide.

EXAMPLE 26 Preparation of 1-( l-isobutyl--nitro-2-imidazolecarboximidoyl)-4-ethyl- 3-thiosernicarbazide Following the general procedure ofExample 24, the

mixed anhydride of N-(p-acetoxybenzoyl)-l-isobutyl-5-nitro-2-imidazolecarboximidic acid and pacetamidobenzoic acid istreated with 4-ethyl-3- thiosemicarbazide to give thel-(l-isobutyl-Snitro-Z-imidazolecarboximidoyl)-4-ethyl-3-thiosemicarbazide.

EXAMPLE 27 Preparation of 2-amino-5-( l-methyl-5-nitro-2- imidazolyl)- l,3 ,4-thiadiazole A mixture of 3.80 grams, 0.0156 mole, ofl-(lmethyl-5-nitro-2-imidazolecarboximidoyl)-3- thiosemicarbazide, 30ml. of methanol, and 12 ml. of 37 percent hydrochloric acid is refluxedfor 1 hour, cooled in ice and filtered. The crystalline residue issuspended in 200 ml. of water, stirred for 2 hours, filtered, washedthoroughly with water, then with four 1- ml. portions of methanol, anddried. There is obtained 2.93 grams of product, m.p. 262264C. (dec.

EXAMPLE 28 The general procedure of Example 27 is repeated using aseries of different starting materials. These starting materials and thecorresponding products are set forth in the following table.

oml llri-om wherein R is lower alkyl, and R is lower alkyl; whichcomprises contacting a compound of the formula:

l v 1 r 01N A N 1 4 R (IV) Starting material Product R R3 R41-(1-methy1-5-nitro-2-imidazolecarboxinxidoyl)4-isopropyl-3-thiosemicarbazideIVa C H; II /C H 3 1-(1-methy1-5-nitro-2-imidazo1ecarboximidoyl)4.4-diethyl-3-thiosemicarbazide.IV CH; C 115 C H1-(l-ethy1-5'nitr0-Q-imidazolecarhoximidoylJ-B-Lhiosemicarbazide Ive C HH H1-(l-ethy1-5-nitro-2-imidazolecarboXimidoyl)-1,Mimethyl-B-thiosemicarbazideIVd C 11 C H; CH;

1- (1-isopropyl-5-nitr0-2-imidazolecarboximidoyl)-4methyl-B-thiosemicarbazidelVc C H; II C H;

1-(1-isobuty1-5-nitro-Z-imldazolecarboximidoyl)+ethyl-3-thiosemicarbazldeU 1V1 OH; 11 C 11;

C H1 C H EXAMPLE 29 Preparation of 2-amino-5-( l-methyl-5-nitro-2-imidazolyhl ,3 ,4-thiadiazole A mixture of ml. of methanol, 1.40 grams,0.026 mole, of sodium methoxide and 7.56 grams, 0.020 mole, of the mixedanhydride of N-benzoyll-methyl-S- nitro-2-imadazolecarboximidic acid andbenzoic acid is stirred at room temperature for 3 hours.Thiosemicarbazide, 1.82 grams, 0.020 mole, and 3 ml. of glacial aceticacid are added and the reaction mixture is al-

2. The process in accordance with claim 1 wherein R is methyl, R1 isphenyl, R2 is phenyl and the strong base is sodium methoxide.